The present invention relates to antibiotic compounds and in particular to antibiotic compounds containing an oxazolidinone ring. This invention further relates to processes for their preparation, to intermediates useful in their preparation, to their use as therapeutic agents and to pharmaceutical compositions containing them.
The international microbiological community continues to express serious concern that the evolution of antibiotic resistance could result in strains against which currently available antibacterial agents will be ineffective. In general, bacterial pathogens may be classified as either Gram-positive or Gram-negative pathogens. Antibiotic compounds with effective activity against both Gram-positive and Gram-negative pathogens are generally regarded as having a broad spectrum of activity. The compounds of the present invention are regarded primarily as effective against Gram-positive pathogens because of their particularly good activity against such pathogens.
Gram-positive pathogens, for example Staphylococci, Enterococci, Streptococci and mycobacteria, are particularly important because of the development of resistant strains which are both difficult to treat and difficult to eradicate from the hospital environment once established. Examples of such strains are methicillin resistant staphylococcus (MRSA), methicillin resistant coagulase negative staphylococci (MRCNS), penicillin resistant streptococcus pneumoniae and multiply resistant Enterococcus faecium.
The major clinically effective antibiotic for treatment of such resistant Gram-positive pathogens is vancomycin. Vancomycin is a glycopeptide and is associated with nephrotoxicity and ototoxicity. Furthermore, and most importantly, antibacterial resistance to vancomycin and other glycopeptides is also appearing. This resistance is increasing at a steady rate rendering these agents less and less effective in the treatment of Gram-positive pathogens.
The present inventor has discovered a class of antibiotic compounds containing an oxazolidinone ring which has useful activity against Gram-positive pathogens including MRSA and MRCNS and, in particular, against various strains exhibiting resistance to vancomycin and against E. faecium strains resistant to both aminoglycosides and clinically used xcex2-lactams.
We have now discovered a range of compounds that have good activity against a broad range of Gram-positive pathogens including organisms known to be resistant to most commonly used antibiotics. In comparison with compounds described in the art (Walter A. Gregory et al, J. Med. Chem., 1990, 33, 2569-2578 and Chung-Ho Park et al, J. Med. Chem., 1992, 35, 1156-1165) the compounds also possess a favourable toxicological profile.
Accordingly the present invention provides a compound of formula (I), 
wherein:
A is linked via a ring carbon atom and is a 5 membered heteroaryl ring containing one nitrogen atom and optionally 1-3 further heteroatoms chosen from oxygen, sulfur and nitrogen, or a bicyclic benzo system containing such a 5 membered heteroaryl ring and is linked via a ring carbon atom in the 5 membered heteroaryl ring, or A is a bicyclic or tricyclic heteroaryl ring system with at least one bridgehead nitrogen and optionally a further 1-3 heteroatoms chosen from oxygen, sulfur and nitrogen and is linked via a ring carbon atom in a ring containing a bridgehead nitrogen;
R1 is attached to a ring carbon atom and is hydroxy, halo, amino, nitro, cyano, carboxy, thiol, C1-4alkanoyloxy, C1-4alkoxycarbonyl, dimethylaminomethyleneaminocarbonyl, C1-4alkyl, C2-4alkenyl, C2-4alkynyl, C1-4alkoxy, R5xe2x80x94, R5xe2x80x94Oxe2x80x94, R5xe2x80x94C1-4alkyl-, R5xe2x80x94C(O)NHxe2x80x94, [where R5 is optionally substituted phenyl, an optionally substituted 5- or 6-membered heteroaryl ring, an optionally substituted 5- or 6-membered heterocycle or an optionally substituted bicyclic heteroaryl ring], hydroxyC1-4alkyl, carbamoyl, Nxe2x80x94(C1-4alkyl)carbamoyl, N,Nxe2x80x94(C1-4alkyl)2carbamoyl, thiocarbamoyl, Nxe2x80x94(C1-4alkyl)thiocarbamoyl, N,Nxe2x80x94(C1-4alkyl)2thiocarbamoyl, trifluoromethyl, C1-4alkanoylamino [where the C1-4alkanoyl group is optionally substituted by hydroxy], R6-thio, R6-sulfinyl, R6-sulfonyl [where R6 is C1-4alkyl optionally substituted by one or more groups independently selected from cyano, hydroxy and C1-4alkoxy], C1-4alkanoyl, sulfonamido, C1-4alkylamino, di(C1-4alkyl)amino, C1-4alkoxyC1-4alkyl, carbamoylC1-4alkyl or cyanoamino, or R1 is attached to a ring nitrogen atom where such substitution does not result in quaternization and is selected from R7xe2x80x94, R7xe2x80x94C(O)xe2x80x94 [where R7 is C1-4alkyl optionally substituted by cyano, hydroxy or C1-4alkoxyl] or C1-4alkoxyC(O)xe2x80x94;
n is 0-6;
R2 and R3 are independently hydrogen or fluoro;
R4 is hydrogen, C1-4alkyl, C1-4alkoxy, amino, chloromethyl, dichloromethyl, cyanomethyl, methoxymethyl, acetylmethyl, methylamino and dimethylamino; or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof.
In this specification the term xe2x80x98alkylxe2x80x99 includes straight chained, branched structures and ring systems. For example, C1-4alkyl includes methyl ethyl, propyl, isopropyl, t-butyl, cyclopropane and cyclobutane; C1-6alkyl includes methyl, ethyl, propyl, isopropyl. t-butyl, cyclopropane and cyclohexane. However, references to individual alkyl groups such as xe2x80x98propylxe2x80x99 are specific for the straight chained version only, references to individual branched chain alkyl groups such as xe2x80x98isopropylxe2x80x99 are specific for the branched chain version only and references to the cyclo groups such as cyclohexane are specific to the cyclic groups only.
A similar convention applies to other radicals, for example xe2x80x9chydroxyC1-4alkylxe2x80x9d includes 1-hydroxyethyl and 2-hydroxyethyl.
The term xe2x80x9chaloxe2x80x9d refers to fluoro, chloro, bromo and iodo.
xe2x80x9cArylxe2x80x9d means phenyl or naphthyl.
xe2x80x9cHeteroarylxe2x80x9d means, unless otherwise further specified, a monocyclic-, bicyclic- or tricyclic-5-14 membered ring that contains some degree of unsaturation, with up to five ring heteroatoms selected from nitrogen, oxygen and sulfur. Examples of xe2x80x9cheteroarylxe2x80x9d include thienyl, furanyl, imidazolyl, thiazolyl, pyrimidinyl, pyridinyl, indolyl, benzimidazolyl, benzthiazolyl, quinolyl, isoquinolinyl, xanthene, phenoxathiin and chromene. Examples of a 5 membered heteroaryl ring containing one nitrogen atom and optionally 1-3 further heteroatoms chosen from oxygen, sulfur and nitrogen include pyrrole, imidazole, triazole, thiazole and isoxazole. Examples of a bicyclic benzo system containing a 5 membered heteroaryl ring containing one nitrogen atom and optionally 1-3 further heteroatoms chosen from oxygen, sulfur and nitrogen include indole, benzothiazole and benzimidazole. Examples of bicyclic or tricyclic heteroaryl ring system with at least one bridgehead nitrogen and optionally a further 1-3 heteroatoms chosen from oxygen, sulfur and nitrogen include 3H-pyrrolo[1,2-a]-pyrrole, pyrrolo[2,1-b]thiazole, 1H-imidazo[1,2-a]pyrrole, 1H-imidazo[1,2-a]imidazole, 1H-pyrrolo[1,2-a]benzimidazole, 9H-imidazo[1,2-a]indole, 5H-imidazo[2,1-a]isoindole, 1H,3H-pyrrolo[1,2-c]oxazole, 1H-imidazo[1,5-a]pyrrole, 1H-imidazo[3,4-a]indole, pyrrolo[1,2-b]isoxazole, imidazo[5,1-b]thiazole, imidazo[2,1-b]thiazole, indolizine, pyrrolo[a]quinoline, 2,3-pyrroloisoquinoline, pyrrolo[a]isoquinoline, imidazo[1,2-a]pyridine, imidazo[1,2-a]quinoline, imidazo[2,1-a]isoquinoline, imidazo[1,5-a]pyridine, imidazo[1,5-a]quinoline, imidazo[5,1-a]isoquinoline, pyrazolo[1,5-a]pyridine, pyrrolo[1,2-b]pyridazine, pyrrolo [1,2-c]pyrimidine, pyrrolo[1,2-a]pyrazine, pyrrolo[1,2-a]pyrimidine, pyrido[2,1-c]-s-triazole, s-triazole[1,5-a]pyridine, imidazo[2,1-c]pyrimidine, imidazo[1,2-a]pyrazine, imidazo[1,2-a]pyrimidine, imidazo[1,5-a]pyrazine, imidazo[1,5-a]pyrimidine, imidazo[1,2-b]-pyridazine, s-triazolo[4,3-a]pyrimidine, imidazo[5,1-b]oxazole and imidazo[2,1-b]oxazole; and partially saturated versions thereof. The nomenclature used is that found in xe2x80x9cHeterocyclic Compounds (Systems with bridgehead nitrogen), W. L. Mosby (Intercsience Publishers Inc., New York), 1961, Parts 1 and 2. Some of the above ring systems are illustrated hereinafter.
xe2x80x9cHeterocyclexe2x80x9d means a mono- or bicyclic-5-10 membered ring, that is totally saturated, with up to five ring heteroatoms selected from nitrogen, oxygen and sulfur. Examples of such heterocycles include morpholine, pyrrolidine, piperazine, imidazoline and piperidine.
Suitable optional substituents for R5 include all of the values of R1 except where R1 includes an R5 group.
An example of xe2x80x9cC1-4alkanoyloxyxe2x80x9d is acetoxy. Examples of xe2x80x9cC1-4alkoxycarbonylxe2x80x9d include methoxycarbonyl, ethoxycarbonyl, n- and t-butoxycarbonyl. Examples of xe2x80x9cC1,4alkylxe2x80x9d include methyl, ethyl, propyl, isopropyl and t-butyl. Examples of xe2x80x9cC2-4alkenylxe2x80x9d include ethenyl and 1-propenyl. Examples of xe2x80x9cC2-4alkynylxe2x80x9d ethynyl and 2-propynyl. Examples of xe2x80x9cC1-4alkoxyxe2x80x9d include methoxy, ethoxy and propoxy. Examples of hydroxy C1-4 alkyl include hydroxymethyl and 2-hydroxyethyl. Examples of xe2x80x9cNxe2x80x94(C1-4alkyl)carbamoylxe2x80x9d include N-methylcarbamoyl, N-ethylcarbamoyl and N-propylcarbamoyl. Examples of xe2x80x9cN,Nxe2x80x94(C1-4alkyl)2carbamoylxe2x80x9d include N,N-dimethylcarbamoyl and N,N-diethylcarbamoyl. Examples of xe2x80x9cNxe2x80x94(C1-4alkyl)thiocarbamoylxe2x80x9d include N-methylthiocarbamoyl. N-ethylthiocarbamoyl and N-propylthiocarbamoyl. Examples of xe2x80x9cN,Nxe2x80x94(C1-4alkyl)2thiocarbamoylxe2x80x9d include N,N-dimethylthiocarbamoyl and N,N-diethylthiocarbamoyl. Examples of xe2x80x9cC1-4alkanoylaminoxe2x80x9d include formamido, acetamido and propionylamino. Examples ofxe2x80x9cC1-4alkylthioxe2x80x9d (where the C1-4alkyl is optionally substituted by cyano, hydroxy or C1-4alkoxy) include methylthio, 2-hydroxyethylthio, 2,3-dihydroxypropylthio and methoxyethylthio. Examples of xe2x80x9cC1-4alkylsulfinylxe2x80x9d (where the C1-4alkyl is optionally substituted by cyano, hydroxy or C1-4alkoxy) include methylsulfinyl 2-hydroxyethylsulfinyl and methoxyethylsulfinyl. Examples of xe2x80x9cC1-4alkylsulfonylxe2x80x9d (where the C1,4alkyl is optionally substituted by cyano, hydroxy or C1-4alkoxy) include methylsulfonyl 2-hydroxyethylsulfonyl and methoxyethylsulfonyl. Examples ofxe2x80x9cC1-4alkanoylxe2x80x9d include propanoyl and ethanoyl. Examples of xe2x80x9cC1-4alkylaminoxe2x80x9d include methylamino and ethylamino. Examples of xe2x80x9cdi(C1-4alkyl)aminoxe2x80x9d include di-N-methylamino, di-(N-ethyl)amino and N-ethyl-N-methylamino. Examples of xe2x80x9cC1-4alkoxyC1-4alkylxe2x80x9d methoxymethyl and propoxyethyl. Examples of xe2x80x9ccarbamoylC1-4alkylxe2x80x9d are methylcarboxamide and ethylcarboxamide.
The skilled man will appreciate that in this specification quarternization means a ring nitrogen atom with no replaceable hydrogen becoming positively charged by further substitution, by, for example, alkyl or amino.
Suitable pharmaceutically acceptable salts include acid addition salts such as methanesulfonate, fumarate, hydrochloride, hydrobromide, citrate, maleate and salts formed with phosphoric and sulfuric acid. In another aspect suitable salts are base salts such as an alkali metal salt for example sodium, an alkaline earth metal salt for example calcium or magnesium, an organic amine salt for example triethylamine, morpholine, N-methylpiperidine, N-ethylpiperidine, procaine, dibenzylamine, N,N-dibenzylethylamine or amino acids for example lysine. There may be more than one cation or anion depending on the number of charged functions and the valency of the cations or anions. A preferred pharmaceutically acceptable salt is a sodium salt.
However, to facilitate isolation of the salt during preparation, salts which are less soluble in the chosen solvent may be preferred whether pharmaceutically-acceptable or not.
An in vivo hydrolysable ester of a compound of the formula (I) containing carboxy or hydroxy group is, for example, a pharmaceutically acceptable ester which is hydrolysed in the human or animal body to produce the parent acid or alcohol.
Suitable pharmaceutically acceptable esters for carboxy include C1-6alkoxymethyl esters for example methoxymethyl, C1-6alkanoyloxymethyl esters for example pivaloyloxymethyl, phthalidyl esters, C3-8cycloalkoxy-carbonyloxyC1-6alkyl esters for example 1-cyclohexylcarbonyloxyethyl, 1,3-dioxolen-2-onylmethyl esters for example 5-methyl-1,3-dioxolen-2-onylmethyl and C1-6alkoxycarbonyloxyethyl esters for example 1-methoxycarbonyloxyethyl and may be formed at any carboxy group in the compounds of this invention.
An in vivo hydrolysable ester of a compound of the formula (I) containing a hydroxy group includes inorganic esters such as phosphate esters and xcex1-acyloxyalkyl ethers and related compounds which as a result of the in vivo hydrolysis of the ester breakdown to give the parent hydroxy group. Examples of xcex1-acyloxyalkyl ethers include acetoxymethoxy and 2,2-dimethylpropionyloxymethoxy. A selection of in vivo hydrolysable ester forming groups for hydroxy include alkanoyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl, alkoxycarbonyl (to give alkyl carbonate esters) dialkylcarbamoyl and N-(dialkylaminoethyl)-N-alkylcarbamoyl (to give carbamates), dialkylaminoacetyl and carboxyacetyl. Examples of substituents on benzoyl include morpholino and piperazino linked from a ring nitrogen atom via a methylene group to the 3- or 4-position of the benzoyl ring.
As a further feature of the invention there are provided suitable N-oxides of a compound of formula (I). Such N-oxides can be formed on an available ring nitrogen atom by, for example, reaction of the parent compound with an oxidizing agent such as metachloro-perbenzoic acid.
In another aspect there are provided compounds of formula (I) as described above, but wherein R1 when it is C1-4alkanoylamino is not optionally substituted by hydroxy in the C1-4alkanoyl group; and where R6 is C1-4alkyl optionally substituted by cyano, hydroxy or C1-4alkoxy.
In another aspect there are provided compounds of formula (I) as described anywhere above, but wherein R1 is not dimethylaminomethyleneaminocarbonyl.
Particularly preferred compounds of the invention comprise a compound of formula (I), or a pharmaceutically-acceptable salt or in vivo hydrolysable ester thereof, wherein R1, R2, R3, R4, A and n have the values disclosed hereinbefore, or any of the following values:
Suitably R5 is monosubstituted by any of the values for R1 (excluding those where R1 includes an R5 group). Preferably R5 is unsubstituted.
R1 is preferably halo in particular fluoro, chloro or bromo.
R1 is also preferably amino, (1-4C)alkyl, (1-4C)alkanoylamino (optionally substituted by hydroxy) cyano, nitro, trifluoromethyl, benzyloxy, (1-4C)alkoxycarbonyl, phenyl, hydroxy. dimethylaminomethyleneaminocarbonyl, (1-4C)alkylthio (optionally substituted by one or two hydroxy groups), (1-4C)alkylsulfinyl, (1-4C)alkylsulfonyl or hydroxy-(1-4C)alkyl.
In one aspect of the invention, preferably at least one of R2 and R3 are hydrogen, in particular one of R2 or R3 is hydrogen and the other is fluoro. In another aspect of the invention preferably both R2 and R3 are fluoro, or both are hydrogen.
R4 is preferably hydrogen or C1-4alkyl, in particular C1-4alkyl, preferably methyl and ethyl and especially methyl.
When ring A is a bicyclic or tricyclic ring system it preferably has one bridgehead nitrogen and optionally a further 1-3 heteroatoms chosen from sulfur and nitrogen, especially nitrogen.
Ring A is preferably a 5,5- or 5,6-fused ring system with at least one bridgehead nitrogen. When ring A is a 5,6-ring system it is preferably an imidazopyridine ring system, in particular imidazo[1,2-a]pyridine or imidazo[1,5-a]pyridine, especially imidazo[1,2-a]pyridine. Also preferred are imidazopyrimidine ring systems, for example imidazo[1,2-c]pyrimidine, imidazo[1,2-a]pyrimidine and imidazol[1,5-a]pyrimidine, especially imidazo[1,2-a]pyrimidine. Preferably such ring systems are linked in the 3-position to the carbonyl group. When A is a 5,5-ring system it is preferably an imidazooxazole or imidazothiazole ring system, in particular imidazo[5,1-b]thiazole, imidazo[2,1-b]thiazole, imidazo[5,1-b]oxazole or imidazo[2,1-b]oxazole, especially imidazo[5,1-b]thiazole or imidazo[2,1-b]thiazole.
Preferably n is 1 or 0, particularly 1.
Therefore a preferred class of compounds is that of formula (Ixe2x80x2): 
wherein:
Ra is halo, amino, (1-4C)alkyl, (1-4C)alkanoylamino (optionally substituted by hydroxy) cyano, nitro, trifluoromethyl, benzyloxy, (1-4C)alkoxycarbonyl, phenyl, hydroxy, dimethylaminomethyleneaminocarbonyl, (1-4C)alkylthio (optionally substituted by one or two hydroxy groups), (1-4C)alkylsulfinyl, (1-4C)alkylsulfonyl, hydroxy-(1,4C)alkyl, [especially halo];
Rb is hydrogen or fluoro;
Rc is hydrogen or fluoro;
Rd is C1-4alkyl;
B is a 5,5- or 5,6- fused ring system with at least one bridgehead nitrogen;
x is 0 or 1 or 2 [especially 0 or 1];
or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof.
Of the above compounds of formula (Ixe2x80x2), preferred values of Ra, Rb, Rc, Rd, B and x are as follows:
Preferably Ra is halo, especially fluoro, chloro or bromo.
In one aspect of the invention, preferably at least one of Rc and Rb are hydrogen, in particular one of Rc or Rb is hydrogen and the other is fluoro. In another aspect of the invention preferably both Rc and Rb are fluoro, or both are hydrogen.
Preferably Rd is methyl. Preferably x is 0 or 1, especially 1.
When B is a 5,6-fused ring system with a bridgehead nitrogen it is preferably an imidazopyridine ring system, in particular imidazo[1,2-a]pyridine or imidazo[1,5-a]pyridine, especially imidazo[1,2-a]pyridine. Also preferred are imidazopyrimidine ring systems, for example imidazo[1,2-c]pyrimidine, imidazo [1,2-a]pyrimidine and imidazo[1,5-a]pyrimidine, especially imidazo[1,2-a]pyrimidine. Preferably such ring systems are linked in the 3-position to the carbonyl group. When B is a 5,5-fused ring system with a bridgehead nitrogen it is preferably an imidazooxazole or imidazothiazole ring system, in particular imidazo[5,1-b]thiazole, imidazo [2,1-b]thiazole, imidazo[5,1-b]oxazole or imidazo[2,1-b]oxazole, especially imidazo[5,1-b]thiazole or imidazo[2,1-b]thiazole linked via the imidazo ring preferably in the position ortho to the bridgehead nitrogen.
The naming and numbering systems of the heteroaryl rings referred to in this specification is that found in xe2x80x9cHeterocyclic Compounds (Systems with bridgehead nitrogen), W. L. Mosby (Intercsience Publishers Inc., New York), 1961, Parts 1 and 2, and is illustrated, but not limited by the following: 
The naming and numbering systems of the heteroaryl rings referred to in this specification is further illustrated, but not limited by the following: 
Preferred compounds having formula (I) include the following (in which the nomenclature used hereinafter refers to the phenyl moiety being linked to the N-position of oxazolidinone ring; an alternative, equivalent, nomenclature would refer to the phenyl moiety being linked to the 3-position of oxazolidinone ring):
N-([(5S)-N-(4-[indolin-3-ylcarbonyl]phenyl)-2-oxooxazolidin-5-yl]methyl)acetamide;
N-([(5S)-N-(4-[6-methylindolizin-3-ylcarbonyl]phenyl)-2-oxooxazolidin-5-yl]methyl)acetamide;
N-([(5S)-N-(4-[6-cyanoindolizin-3-ylcarbonyl]phenyl)-2-oxooxazolidin-5-yl]methyl)acetamide;
N-([(5S)-N-(4-[3-methylpyrrolo[1,2-a]pyrazin-6-ylcarbonyl]phenyl)-2-oxo oxazolidin-5-yl]methyl)acetamide;
N-([(5S)-N-(4-[imidazo[1,2-a]pyridin-3-ylcarbonyl]phenyl)-2-oxooxazolidin-5-yl]methyl)acetamide;
N-([(5S)-N-(4-[imidazo[1,2-a]pyrimidin-3-ylcarbonyl]phenyl)-2-oxooxazolidin-5-yl]methyl)acetamide;
N-([(5S)-N-(4-[5,7-dimethylimidazo[1,2-a]pyrimidin-3-ylcarbonyl]phenyl)-2-oxooxazolidin-5-yl]methyl)acetamide;
N-([(5S)-N-(4-[6-bromoimidazo[1,2-a]pyridin-3-ylcarbonyl]phenyl)-2-oxooxazolidin-5-yl]methyl)acetamide;
N-([(5S)-N-(4-[imidazo[2,1-a]isoquinol-3-ylcarbonyl]phenyl)-2-oxooxazolidin-5-yl]methyl)acetamide.
N-([(5S)-N-(4-[imidazo[2,1-b]thiazol-5-ylcarbonyl]phenyl)-2-oxooxazolidin-5-yl]methyl)acetamide;
N-([(5S)-N-(4-[6,8-dichloroimidazo[1,2-a]pyridin-3-ylcarbonyl]phenyl)-2-oxooxazolidin-5-yl]methyl)acetamide;
N-([(5S)-N-(4-[1-cyanoindolizin-3-ylcarbonyl]phenyl)-2-oxooxazolidin-5-yl]methyl)acetamide;
N-([(5S)-N-(4-[7-methylimidazo[1,2-a]pyridin-3-ylcarbonyl]phenyl)-2-oxooxazolidin-5-yl]methyl)acetamide;
N-([(5S)-N-(4-[6-chloroimidazo[1,2-a]pyridin-3-ylcarbonyl]phenyl)-2-oxooxazolidin-5-yl]methyl)acetamide;
N-([(5S)-N-(4-[6-nitroimidazo[1,2-a]pyridin-3-ylcarbonyl]phenyl)-2-oxooxazolidin-5-yl]methyl)acetamide;
N-([(5S)-N-(4-[8-nitroimidazo[1,2-a]pyridin-3-ylcarbonyl]phenyl)-2-oxooxazolidin-5-yl]methyl)acetamide;
N-([(5S)-N-(4-[5,7-dimethylimidazo[1,2-a]pyridin-3-ylcarbonyl]phenyl)-2-oxooxazolidin-5-yl]methyl)acetamide;
N-([(5S)-N-(4-[5-methylimidazo[1,2-a]pyridin-3-ylcarbonyl]phenyl)-2-oxooxazolidin-5-yl]methyl)acetamide;
N-([(5S)-N-(4-[8-bromo-6-methylimidazo[1,2-a]pyridin-3-ylcarbonyl]phenyl)-2-oxooxazolidin-5-yl]methyl)acetamide;
N-([(5S)-N-(4-[8-benzyloxyimidazo[1,2-a]pyridin-3-ylcarbonyl]phenyl)-2-oxooxazolidin-5-yl]methyl)acetamide;
N-([(5S)-N-(4-[6-trifluoromethylimidazo[1,2-a]pyridin-3-ylcarbonyl]phenyl)-2-oxooxazolidin-5-yl]methyl)acetamide;
N-([(5S)-N-(4-[imidazo[1,2-a]pyridin-3-ylcarbonyl]{3-fluorophenyl})-2-yl]methyl)acetamide;
N-([(5S)-N-(4-[8-methoxycarbonylimidazo[1,2-a]pyridin-3-ylcarbonyl]phenyl)-2-oxooxazolidin-5-yl]methyl)acetamide;
N-([(5S)-N-(4-[6-methoxycarbonylimidazo[1,2-a]pyridin-3-ylcarbonyl]phenyl)-2-oxooxazolidin-5-yl]methyl)acetamide;
N-([(5S)-N-(4-[7-phenylimidazo[1,2-a]pyridin-3-ylcarbonyl]phenyl)-2-oxooxazolidin-5-yl]methyl)acetamide;
N-([(5S)-N-(4-[8-hydroxyimidazo[1,2-a]pyridin-3-ylcarbonyl]phenyl)-2-oxooxazolidin-5-yl]methyl)acetamide;
or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof.
Further preferred compounds having formula (I) include:
N-([(5S)-N-(4-[imidazo[2,1-b]oxazol-5-ylcarbonyl]phenyl)-2-oxooxazolidin-5-yl]methyl)acetamide;
N-([(5S)-N-(4-[1-methylimidazo[1,2-a]pyrrol-5-ylcarbonyl]phenyl)-2-oxooxazolidin-5-yl]methyl)acetamide;
N-([(5S)-N-(4-[6-cyanoimidazo[1,2-a]pyridin-3-ylcarbonyl]phenyl)-2-oxooxazolidin-5-yl]methyl)acetamide;
N-([(5S)-N-(4-[pyrrol-2-ylcarbonyl]phenyl)-2-oxooxazolidin-5-yl]methyl)acetamide;
N-([(5S)-N-(4-[1-hydroxymethylcarbonylpyrrol-2-ylcarbonyl]phenyl)-2-oxooxazolidin-5-yl]methyl)acetamide;
N-([(5S)-N-(4-[imidazol-2-ylcarbonyl]phenyl)-2-oxooxazolidin-5-yl]methyl)acetamide;
N-([(5S)-N-(4-[1-hydroxymethylcarbonylimidazol-2-ylcarbonyl]phenyl)-2-oxooxazolidin-5-yl]methyl)acetamide;
N-([(5S)-N-(4-[imidazo[1,2-a]pyridin-2-ylcarbonyl]phenyl)-2-oxooxazolidin-5-yl]methyl)acetamide;
N-([(5S)-N-(4-[imidazo[2,1-b]thiazol-5-ylcarbonyl]{3-fluorophenyl})-2-oxooxazolidin-5-yl]methyl)acetamide;
or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof.
Yet further preferred compounds having formula (I) include:
N-([(5S)-N-(4-[6-fluoroimidazo[1,2-a]pyridin-3-ylcarbonyl]phenyl)-2-oxooxazolidin-5-yl]methyl)acetamide;
N-([(5S)-N-(4-[6-cyanoimidazo[1,2-a]pyridin-3-ylcarbonyl]phenyl)-2-oxooxazolidin-5-yl]methyl)acetamide;
N-([(5S)-N-(4-[1-methylimidazo[1,2-a]imidazol-5-ylcarbonyl]phenyl)-2-oxooxazolidin-5-yl]methyl)acetamide;
N-([(5S)-N-(4-[2.3-dihydroimidazo[2,1-b]thiazol-5-ylcarbonyl]phenyl)-2-oxooxazolidin-5-yl]methyl)acetamide;
N-([(5S)-N-(4-[6-{dimethylaminomethyleneaminocarbonyl}imidazo[1,2-a]pyridin-3-ylcarbonyl]phenyl)-2-oxooxazolidin-5-yl]methyl)acetamide;
N-([(5S)-N-(4-[thiazol-2-ylcarbonyl]phenyl)-2-oxooxazolidin-5-yl]methyl)acetamide;
N-([(5S)-N-(4-[benzothiazol-2-ylcarbonyl]phenyl)-2-oxooxazolidin-5-yl]methyl)acetamide;
or a pharmaceutically acceptable salt thereof.
Yet further preferred compounds having formula (I) include:
N-([(5S)-N-(4-[6-aminoimidazo[1,2-a]pyridin-3-ylcarbonyl]phenyl)-2-oxooxazolidin-5-yl]methyl)acetamide;
N-([(5S)-N-(4-[6-acetamidoimidazo[1,2-a]pyridin-3-ylcarbonyl]phenyl)-2-oxooxazolidin-5-yl]methyl)acetamide;
N-([(5S)-N-(4-[6-(hydroxyacetamido)imidazo[1,2-a]pyridin-3-ylcarbonyl]phenyl)-2-oxooxazolidin-5-yl]methyl)acetamide;
N-([(5S)-N-(4-[6-methylthioimidazo[1,2-a]pyridin-3-ylcarbonyl]phenyl)-2-oxooxazolidin-5-yl]methyl)acetamide;
N-([(5S)-N-(4-[6-(methylsulfinyl)imidazo[1,2-a]pyridin-3-ylcarbonyl]phenyl)-2-oxooxazolidin-5-yl]methyl)acetamide;
N-([(5S)-N-(4-[6-(methylsulfonyl)imidazo[1,2-a]pyridin-3-ylcarbonyl]phenyl)-2-oxooxazolidin-5-yl]methyl)acetamide;
N-([(5S)-N-(4-[6-(2-hydroxyethylthio)imidazo[1,2-a]pyridin-3-ylcarbonyl]phenyl)-2-oxooxazolidin-5-yl]methyl)acetamide;
N-([(5S)-N-(4-[6-(2,3-dihydroxypropylthio)imidazo[1,2-a]pyridin-3-ylcarbonyl]phenyl)-2-oxooxazolidin-5-yl]methyl)acetamide;
N-([(5S)-N-(4-[6-hydroxymethylimidazo[1,2-a]pyridin-3-ylcarbonyl]phenyl)-2-oxooxazolidin-5-yl]methyl)acetamide;
N-([(5S)-N-(4-[6-bromoimidazo[1,2-a]pyrazin-3-ylcarbonyl]phenyl)-2-oxooxazolidin-5-yl]methyl)acetamide;
N-([(5S)-N-(4-[6-chloroimidazo[1,2-b]pyridazine-3-ylcarbonyl]phenyl)-2-oxooxazolidin-5-yl]methyl)acetamide;
N-([(5S)-N-(4-[imidazo[1,2-a]pyrazin-3-ylcarbonyl]phenyl)-2-oxooxazolidin-5-yl]methyl)acetamide;
N-([(5S)-N-(4-[6-chloroimidazo[1,2-a]pyrimidin-3-ylcarbonyl]phenyl)-2-oxooxazolidin-5-yl]methyl)acetamide;
N-([(5S)-N-(4-[pyrrol-2-ylcarbonyl]phenyl)-2-oxooxazolidin-5-yl]methyl)acetamide;
N-([(5S)-N-(4-[1-methylpyrrol-2-yl carbonyl]phenyl)-2-oxooxazolidin-5-yl]methyl)acetamide;
N-([(5S)-N-(4-[imidazol-2-ylcarbonyl]phenyl)-2-oxooxazolidin-5-yl]methyl)acetamide;
N-([(5S)-N-(4-[1-methylimidazol-2-ylcarbonyl]phenyl)-2-oxooxazolidin-5-yl]methyl)acetamide; or a pharmaceutically acceptable salt thereof.
Especially preferred compounds having formula (I) are:
N-([(5S)-N-(4-[6-fluoroimidazo[1,2-a]pyridin-3-ylcarbonyl]phenyl)-2-oxooxazolidin-5-yl]methyl)acetamide;
N-([(5S)-N-(4-[6-chloroimidazo[1,2-a]pyridin-3-ylcarbonyl]phenyl)-2-oxooxazolidin-5-yl]methyl)acetamide; or a pharmaceutically acceptable salt thereof.
Further especially preferred compounds having formula (I) are:
N-([(5S)-N-(4-[imidazo[1,2-a]pyrazin-3-ylcarbonyl]phenyl)-2-oxooxazolidin-5-yl methyl)acetamide;
N-([(5S)-N-(4-[6-chloroimidazo[1,2-a]pyrimidin-3-ylcarbonyl]phenyl)-2-oxooxazolidin-5-yl]methyl)acetamide;
N-([(5S)-N-(4-[6-(2-hydroxyethylthio)imidazo[1,2-a]pyridin-3-ylcarbonyl]phenyl)-2-oxooxazolidin-5-yl]methyl)acetamide;
N-([(5S)-N-(4-[6-fluoroimidazo[1,2-a]pyridin-3-ylcarbonyl]phenyl)-2-oxooxazolidin-5-yl)methyl)acetamide;
N-([(5S)-N-(4-[imidazo[1,2-a]pyridin-3-ylcarbonyl]{3-fluorophenyl})-2-oxooxazolidin-5-yl]methyl)acetamide;
N-([(5S)-N-(4-[6-chloroimidazo[1,2-a]pyridin-3-ylcarbonyl]phenyl)-2-oxooxazolidin-5-yl]methyl)acetamide;
N-([(5S)-N-(4-[imidazo[2,1-b]thiazol-5-ylcarbonyl]phenyl)-2-oxooxazolidin-5-yl]methyl)acetamide;
N-([(5S)-N-(4-[6-bromoimidazo[1,2-a]pyridin-3-ylcarbonyl]phenyl)-2-oxooxazolidin-5-yl]methyl)acetamide.
Also especially preferred is the compound of formula (I) being:
N-([(5S)-N-(4-[6-fluoroimidazo[1,2-a]pyrimidin-3-ylcarbonyl]phenyl)-2-oxooxazolidin-5-yl]methyl)acetamide.
The compounds of the present invention have a chiral centre at the C-5 position of the oxazolidinone ring. The pharmaceutically active enantiomer is of formula (IA): 
The present invention includes the pure 5S enantiomer depicted above or mixtures of the 5R and 5S enantiomers, for example a racemic mixture. In a pharmaceutical composition if a mixture of enantiomers is used, a larger amount (depending upon the ratio of the enantiomers) will be required to achieve the same effect as the same weight of the pharmaceutically active enantiomer.
Some compounds of formula (I) may possess other chiral centres. It is to be understood that the invention encompasses all such optical isomers and diasteroisomers of compounds of formula (I).
The invention further relates to all tautomeric forms of the compounds of formula (I) that possess antibacterial activity.
It is also to be understood that certain compounds of the formula (I) can exist in solvated as well as unsolvated forms such as, for example, hydrated forms. It is to be understood that the invention encompasses all such solvated forms that possess antibacterial activity.
Another aspect of the present invention provides a process for preparing a compound of formula (I), or a pharmaceutically acceptable salt or an in vivo hydrolysable ester thereof (where R1, R2, R3, R4 and n are as defined for formula (I) which comprises the following processes (a) to (i):
a) reacting a compound of formula (II) 
xe2x80x83where L is a leaving group, with a compound of formula (III) 
xe2x80x83where Y1 is a mono- or bicyclic-heteroaryl ring containing at least one nitrogen atom that is capable of quaternizing with (II) and the Me group is ortho to this nitrogen, in the presence of dimethylformamide dimethylacetal (DMFDMA) (IV) 
xe2x80x83to give a compound of formula (V) 
b) reacting a compound of formula (II) with a compound of formula (VI) 
xe2x80x83where Y1 is as defined above and the NH2 group is ortho to the nitrogen that is capable of quaternizing with (II), in the presence of DMFDMA (IV) to give a compound of formula (VII) 
c) reacting a compound of formula (II) with a compound of formula (VIII) 
xe2x80x83where Y2 is a mono- or bicyclic- heteroaryl ring containing at least one nitrogen atom that is capable of quaternizing with (II), followed by reaction with a compound of formula (IX) or an acetylene of formula (IXa)

xe2x80x83where X is an electron withdrawing group within the definition of R1 for formula (I) (such as cyano, nitro or C1-4alkanoyl) and Qa is hydrogen or a group within the definition of R1, to give a compound of formula (X) 
d) reacting a compound of formula (XI) 
xe2x80x83where L is as defined above, with a compound of formula (VI) to give a compound of formula (XII) 
e) reacting a compound of formula (XIII) 
xe2x80x83with a compound of formula (XIV) 
xe2x80x83where Y3 is a nitrogen-containing 5 membered heteroaryl ring or a nitrogen-containing 5 membered heteroaryl ring fused to a benzo ring which together form a bicyclic heteroaryl ring system without a bridgehead nitrogen, or Y3 is a bicyclic or tricyclic heteroaryl ring system with at least one bridgehead nitrogen, and optionally with a further 1-3 heteroatoms chosen from oxygen, sulfur and nitrogen, to give a compound of formula (XV) 
f) reacting a compound of formula (XVI) 
xe2x80x83where Y4 is a mono- or bicyclic-heteroaryl ring containing at least one nitrogen atom that is capable of forming a quaternary complex with the NH2 group which is attached to this nitrogen and Q is a counter ion, with a compound of formula (XVII) 
xe2x80x83to give a compound of formula (XVIII) 
g) reacting a compound of formula (XIX) 
xe2x80x83where Y5 is a mono- or bicyclic-heteroaryl ring containing at least one nitrogen atom that is capable of quaternization, and the xe2x80x94CH2xe2x80x94C(O)xe2x80x94 linking group is ortho to this nitrogen in the heteroaryl ring, with p-toluenesulfonylazide to give a compound of formula (XX) 
h) reacting a compound of formula (XI) with a compound of formula (XVI) to give a compound of formula (XXI) 
xe2x80x83or
i) For compounds of formula (I) in which A is thiazole or contains a thiazole moiety and is linked via the 2-position of said thiazole, by reaction of a compound of formula (II) with the parent thiazole compound; wherein:
L is a leaving group for example chloro, bromo, iodo, triflate or tosylate. Preferably L is bromo;
Y1 is a mono- or bicyclic-heteroaryl ring containing at least one nitrogen atom that is capable of quaternizing. Where Y1 contains more than one nitrogen atom preferably the molecule is symmetrical. Preferably Y1 is pyridine, pyrimidine, pyridazine, pyrazine, thiazole, oxazole or N-substituted imidazole;
Y2 is a mono- or bicyclic-heteroaryl ring containing at least one nitrogen atom that is capable of quaternizing. Preferably Y2 is pyridine, pyrimidine, pyridazine, pyrazine, thiazole, oxazole or N-substituted imidazole;
Y3 is a nitrogen-containing 5 membered heteroaryl ring or a nitrogen-containing 5 membered heteroaryl ring fused to a phenyl ring or Y3 is a bicyclic or tricyclic heteroaryl ring system with at least one bridgehead nitrogen, and optionally with a further 1-3 heteroatoms chosen from oxygen, sulfur and nitrogen. Preferably Y3 is pyrrole, imidazole, indole thiazole, oxazole or N-substituted imidazole;
Y4 is a mono- or bicyclic-heteroaryl ring containing at least one nitrogen atom that is capable of quaternizing. Preferably Y4 is pyridine, pyrimidine, pyridazine, pyrazine, thiazole, oxazole or N-substituted imidazole;
Y5 is a mono- or bicyclic-heteroaryl ring containing at least one nitrogen atom that is capable of quaternizing. Preferably Y5 is pyridine, pyrimidine, pyridazine, pyrazine, thiazole, oxazole or N-substituted imidazole;
Q is a counter ion. Preferably Q is chloro, bromo or iodo;
X is an electron withdrawing group. Preferably X is cyano;
Qa is hydrogen or a group within the definition of R1. Preferably Qa is hydrogen; and thereafter if necessary
i) forming a pharmaceutically acceptable salt,
ii) forming an in vivo hydrolysable ester or
iii) forming a suitable N-oxide.
The skilled reader will appreciate that not all nitrogen containing heteroaryl rings contain a nitrogen that is capable of quaternizing, for example the nitrogen in pyrrole cannot.
Specific reaction conditions for the above reactions are as follows:
a) Compounds of formula (II) and compounds of formula (III) are reacted together in the presence of an inert solvent (such as N,N-dimethylformamide, toluene or dioxan) at a temperature of 50-200xc2x0 C., preferably 100-130xc2x0 C. DMFDMA (IV) is then added and the mixture heated at a temperature of 50-200xc2x0 C., preferably 150-180xc2x0 C.
DMFDMA (IV) is commercially available and compounds of formula (III) are known, or are commercially available, or they may be prepared by standard manipulation of commercially available or known materials. Examples of these procedures for heterocyclic compounds are given in xe2x80x9cThe chemistry of heterocyclic compoundsxe2x80x9d published by Interscience and Houben-Weyl, Methoden der organischem chime, Heterarene III Teil 3, ed. E. Schaumann (1994).
N-(5S)-3-(4-[bromoacetyl]phenyl)-2-oxooxazolidin-5-ylmethylacetamide (XXII) 
is a known compound (Britelli et. al., J. Med. Chem., 1990, 33, 2569-2578).
N-(5S)-3-(4-[bromoacetyl]-3-fluorophenyl)-2-oxooxazolidin-5-ylmethylacetamide may be prepared by stirring N-(5S)-3-(4-acetyl-3-fluorophenyl)-2-oxooxazolidin-5-ylmethylacetamide (XXIII) 
with bromine in an organic acid (such as acetic acid) with a catalyst (such as methane sulfonic acid) at a temperature of 5-50xc2x0 C., preferably 15-30xc2x0 C. Compound (XXIII) is a known compound (J. Med. Chem., 1992, 35(6), 1156-65).
N-(5S)-3-(4-[bromoacetyl]-3,5-difluorophenyl)-2-oxooxazolidin-5-ylmethylacetamide may be prepared by brominating N-(5S)-3-(4-acetyl-3,5-difluorophenyl)-2-oxooxazolidin-5-ylmethylacetamide (XXIV) 
with bromine in an organic acid (such as acetic acid) with a catalyst (such as methane sulfonic acid) at a temperature of 5-50xc2x0 C., preferably 15-30xc2x0 C.
N-(5S)-3-(4-acetyl-3,5-difluorophenyl)-2-oxooxazolidin-5-ylmethylacetamide may be prepared by reacting N-(5S)-3-(4-iodo-3,5-difluorophenyl)-2-oxooxazolidin-5-ylmethylacetamide (XXV) 
with butyl vinyl ether and a palladium catalyst under standard conditions (for example J. Org. Chem., 1992, 5, 1481-1486). Compound (XXV) is a known compound (WO 94/13649 A1).
b) Compounds of formula (VI) are heated with DMFDMA (IV) in an inert solvent (such as toluene). The inert solvent is removed and the residue is redissolved in a polar solvent (such as N,N-dimethylformamide or dimethylacetamide or an alcohol (such as MeOH or EtOH)) with the compound of formula (II) and heated at 40-120xc2x0 C., such as 60-120xc2x0 C., preferably 80-100xc2x0 C.
Compounds of formula (VI) are known, or are commercially available, or they may be prepared by standard manipulation of commercially available or known materials. Examples of these procedures for heterocyclic compounds are given in xe2x80x9cThe chemistry of heterocyclic compoundsxe2x80x9d published by Interscience and Houben-Weyl, Methoden der organischem chime, Heterarene III Teil 3, ed.
c) Compounds of formula (II) and compounds of formula (VIII) are heated together in the presence of an alcohol (such as EtOH) at 50-100xc2x0 C., preferably at or near 80xc2x0 C. The resulting compound is heated with a compound of formula (IX) with an oxidation catalyst (such as tetrapyridylcobalt dichromate; Xudong et al, J. Chem. Soc., 1993, 2487), or with a compound of formula (IXa) in the absence of an oxidation catalyst, and a catalytic quantity of a weak base (such as pyridine) in an inert solvent (such as N,N-dimethylformamide) at a temperature of 70-110xc2x0 C., preferably 80-100xc2x0 C.
Compounds of formula (VIII), (IX) and (IXa) are known, or are commercially available, or they may be prepared by standard manipulation of commercially available or known materials. Examples of these procedures for heterocyclic compounds are given in xe2x80x9cThe chemistry of heterocyclic compoundsxe2x80x9d published by Interscience and Houben-Weyl, Methoden der organischem chime, Heterarene III Teil 3, ed. In process c) it will be appreciated that compounds of formula (IX) may be in cis- or trans- orientation.
d) Compounds of formula (XI) and compounds of formula (VI) are reacted together under standard conditions (for example J. Het. Chem., 1989, 26, 293; J. Med. Chem., 1988, 31(6), 1220-6) for example heating together in a solvent (such as N,N-dimethylformamide or THF/EtOH) at or near the boiling point of the solvent in the presence of a base (such as sodium carbonate or triethylamine).
Compounds of formula (XI) may be prepared, for example, by brominating compounds of formula (XXVI) 
under standard conditions (for example Org. Synth., 1943, 480). Compounds of formula (XXVI) may be prepared by oxidising compounds of formula (XXVII) 
under standard conditions (for example Tet. Lett., 1977, 695). Compounds of formula (XXVII) may be prepared by acylating a compound of formula (XXVIII) 
under standard Friedel Crafts conditions with propionic anhydride with methane sulfonic acid as the Lewis acid (for example J. Med. Chem., 1989, 32, 1673). Compounds of formula (XXVIII) are known compounds (J. Med. Chem., 1989, 32, 1673) or may be prepared by methods analogous to those disclosed in the reference.
e) Compounds of formula (XIII) and compounds of formula (XIV) are reacted together under standard conditions (for example: Eur. J. Med. Chem.-Chim. Ther,., 1983, 18(4), 339-346).
Compounds of formula (XIII) may be prepared by chlorinating compounds of formula (XXIX) 
under standard conditions. Compounds of formula (XXIX) may be prepared by the hydrolysis of the corresponding alkyl ester compounds known in the literature (for example J. Med. Chem., 1990, 33, 2569-78) or they may be prepared by an analogous method to that disclosed in the reference. Compounds of formula (XIV) are known, or are commercially available, or they may be prepared by standard manipulation of commercially available or known materials. Examples of these procedures for heterocyclic compounds are given in xe2x80x9cThe chemistry of heterocyclic compoundsxe2x80x9d published by Interscience and Houben-Weyl, Methoden der organischem chime, Heterarene III Teil 3, ed.
Compounds of formula (XV) with a suitable R1 substituent can optionally be further manipulated by processes known in the art to form further compounds of formula (I) where A is an F,P-ring system where F is a monocyclic or bicyclic heteroaryl ring and P is the pyrrole ring by suitable manipulation of the R1 substituent. Thus, monocyclic pyrrole rings may, for example, be converted into bicyclic ring systems for example pyrrolothiazole.
f) Compounds of formula (XVI) and compounds of formula (XVII) are reacted together under standard conditions (for example: J. Het. Chem., 1988, 25, 327).
Compounds of formula (XVII) may be prepared by oxidising compounds of formula (XXX) 
Compounds of formula (XXX) may be prepared by reacting compounds of formula (XXXI) 
with ethynylmagnesium bromide under standard Grignard conditions (for example Synlett., 1993, 4, 281-2).
Compounds of formula (XXXI) are known in the literature (for example J. Med. Chem., 1990, 33, 2569-78) or may be prepared by an analogous method to that disclosed in the reference. Compounds of formula (XVI) are known, or are commercially available, or they may be prepared by standard manipulation of commercially available or known materials (for example Tet. Lett, 1972, 4133).
g) Compounds of formula (XIX) and p-toluenesulfonylazide (Synth Commun., 1987, 17, 1015) are reacted together under standard conditions (for example Chem. Ber., 1966, 99, 2918).
Compounds of formula (XIX) may be prepared by reacting compounds (XXII), (XXIII) or (XXIV), or analogous compounds, with compounds of formula (XXXII) 
where L is a leaving group as defined above and is ortho to the ring nitrogen that is capable of quaternization, under standard conditions (for example Tet., Lett., 1994, 5185). Compounds of formula (XXII) are known, or are commercially available, or they may be prepared by standard manipulation of commercially available or known materials. Examples of these procedures for heterocyclic compounds are given in xe2x80x9cThe chemistry of heterocyclic compoundsxe2x80x9d published by Interscience and Houben-Weyl, Methoden der organischem chime, Heterarene III Teil 3, ed.
h) Compounds of formula (XI) and compounds of formula (XVI) are reacted together under standard conditions for example conditions similar to that disclosed in f).
i) Compounds of formula (II) and a parent thiazole compound as described in process i) are reacted in a solvent such as DMF, EtOH or MeOH at a temperature in the range ambient to 100xc2x0 C. to give a quarternary compound; followed by treatment with at, or near, 2 mol.equivalents of aqueous sodium hydroxide (approximately 8%) in a solvent such as MeOH or EtOH (Ref. Singh et al, Ind.J.Chem., 31B, 217 (1992). DMFDMA is not necessary for this reaction.
The processes above were illustrated for the cases where L as defined in formula (II) and (XI) was bromine and R4 as defined in formula (I) was methyl. It will be appreciated by the reader that in compounds where L and R4 are other than these values the corresponding compounds can be prepared by conventional functional group modifications within the skill of the ordinary organic chemist. The processes a)-i) described above with other values for L and R4 are a further feature of the invention. Furthermore. certain intermediate compounds described in the above processes are novel and are provided as a further feature of the invention.
The R4 substituent may be introduced from compounds of formula (XXXIII) 
in the following manner:
i) When R4 is C1-4alkyl, the group xe2x80x94C(xe2x95x90O)C1-4alkyl may be introduced into a compound of the formula (XXXIII) by standard acetylation procedures. For example, the amino group may be acetylated to give an acetamido group using the Schotten-Baumann procedure i.e. reacting the compound of the formula (XXXIII) with acetic anhydride in aqueous sodium hydroxide and THF in a temperature range of 0xc2x0 C. to ambient temperature. Preferably the acylation is carried out in situ following the catalytic hydrogenation of a compound of the formula (XXXIV) 
xe2x80x83wherein M is azido, by performing the hydrogenation in the presence of acetic anhydride.
ii) When R4 is hydrogen, the xe2x80x94CHO group may be introduced into the compound of the formula (XXXIII) by reacting the latter compound with formic acetic anhydride, in an inert organic solvent (such as THE), in a temperature range of 0xc2x0 C. to ambient temperature, or by reacting it with ethyl formate in an inert organic solvent in the temperature range of 50-100xc2x0 C.
iii) When R4 is C1-4alkoxy, the xe2x80x94CO2C1-4alkyl group may be introduced into the compound of the formula (XXXIII) by reacting the latter compound with C1-4alkyl chloroformate, in the presence of an organic base (such as triethylamine), in an organic solvent such as dichloromethane and in a temperature range of 0xc2x0 C. to ambient temperature.
iv) When R4 is amino, the xe2x80x94CONH2 group may be introduced into the compound of the formula (XXXIII) by reacting the latter compound either with potassium cyanate in aqueous acid (such as hydrochloric acid) in a temperature range of ambient temperature to 40xc2x0 C. or with phenyl carbamate in glyme at reflux.
v) When R4 is chloromethyl, dichloromethyl, cyanomethyl or methoxymethyl, the xe2x80x94C(O)R4 group may be introduced into the compound of the formula (XXXIII) by reacting the latter compound with the appropriate acid chloride under standard conditions. The acid chloride may be prepared from the appropriate acid. When R4 is acetylmethyl, the xe2x80x94C(O)R4 group may be introduced into the amino compound by reacting the latter compound with diketene, in an inert organic solvent (such as THF), in a temperature range of 0xc2x0 C. to ambient temperature. Alternatively, the compound of the formula (XXXIII) may be reacted with the appropriate acid anhydride, in dichloromethane or THF, in the presence of an organic base such as triethylamine and in a temperature range of 0xc2x0 C. to ambient temperature, or the amino compound may be reacted with the appropriate acid in the presence of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and an organic base (such as triethylamine), in an organic solvent (such as dichloromethane), in a temperature range of 0xc2x0 C. to ambient temperature.
vi) When R4 is methylamino, the xe2x80x94CONHMe group may be introduced into the compound of the formula (XXXIII) by reacting the latter compound with methyl isocyanate in an organic solvent (such as THF or acetonitrile), in a temperature range of 0xc2x0 C. to ambient temperature.
vii) When R4 is dimethylamino, the xe2x80x94CONMe2 group may be introduced into the compound by of the formula (XXXIII) by reacting the latter compound with dimethylcarbamoyl chloride and triethylamine in an organic solvent (such as THF or acetonitrile), in a temperature range of 0xc2x0 C. to ambient temperature.
Compounds of formula (XXXIII) may be prepared from compounds of formula (XXVIII) by cleavage of the acetamide with acid under standard conditions.
Compounds of formula XXXIII in which a suitable R4 has been introduced may be subsequently modified to give the intermediates required by processes a)-i) using standard chemical modifications.
It will be appreciated by the reader that procedures for manipulation of R4 as set out above can also be used on other compounds used or synthesised in procedures a)-i) with protection of functional groups where necessary, to make other compounds or formula (I).
Processes a)-i) describe the assembly of the ring A as the final as the final stage in the synthesis. It will be appreciated that the ring A may also be assembled at an earlier stage by reaction of a suitable heterocycle with, for example, 4-nitrobenzoyl chloride, followed by reduction of the nitro group to an amino group which can then be elaborated into a suitable 5-substituted oxazolidin-2-one ring using known chemistry (see for example, WO97/37980 and the references cited thereinxe2x80x94the contents of which are hereby incorporated by reference).
It will be appreciated that certain of the various optional substituents R1 in the compounds of the present invention may be introduced by standard aromatic substitution reactions or generated by conventional functional group modifications either prior to or immediately following the processes mentioned above, and as such are included in the process aspect of the invention. Such reactions and modifications include, for example, introduction of a substituent by means of an aromatic substitution reaction, reduction of substituents, alkylation of substituents and oxidation of substituents. The reagents and reaction conditions for such procedures are well known in the chemical art. Particular examples of aromatic substitution reactions include the introduction of a nitro group using concentrated nitric acid, the introduction of an acyl group using, for example an acyl halide and Lewis acid (such as aluminium trichloride) under Friedel Crafts conditions; the introduction of an alkyl group using an alkyl halide and Lewis acid (such as aluminium trichloride) under Friedel Crafts conditions; and the introduction of a halogeno group. Particular examples of modifications include the reduction of a nitro group to an amino group by for example, catalytic hydrogenation with a nickel catalyst or treatment with iron in the presence of hydrochloric acid with heating; conversion of amino to alkanoylamino; oxidation of alkylthio to alkylsulfinyl or alkylsulfonyl; hydrogenation of halo to hydrogen.
Where ring A, as defined in formula (I), is a partially saturated ring system, it may be obtained by hydrogenation of the corresponding unsaturated ring system by techniques known in the art, for example catalytic hydrogenation in the presence of a transition metal catalyst or chemical hydrogenation for example with sodium and ammonia.
It will also be appreciated that in some of the reactions mentioned herein it may be necessary/desirable to protect any sensitive groups in the compounds (see, for example, Examples 47 and 49 where a protecting group is used to ensure reaction occurs at the desired centre). The instances where protection is necessary or desirable and suitable methods for protection are known to those skilled in the art. Thus, if reactants include groups such as amino, carboxy or hydroxy it may be desirable to protect the group in some of the reactions mentioned herein.
A suitable protecting group for an amino or alkylamino group is, for example, an acyl group, for example an alkanoyl group such as acetyl, an alkoxycarbonyl group, for example a methoxycarbonyl, ethoxycarbonyl or t-butoxycarbonyl group, an arylmethoxycarbonyl group, for example benzyloxycarbonyl, or an aroyl group, for example benzoyl. The deprotection conditions for the above protecting groups necessarily vary with the choice of protecting group. Thus, for example, an acyl group such as an alkanoyl or alkoxycarbonyl group or an aroyl group may be removed for example, by hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide. Alternatively an acyl group such as a t-butoxycarbonyl group may be removed, for example, by treatment with a suitable acid as hydrochloric, sulfuric or phosphoric acid or trifluoroacetic acid and an arylmethoxycarbonyl group such as a benzyloxycarbonyl group may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon, or by treatment with a Lewis acid for example boron tris(trifluoroacetate). A suitable alternative protecting group for a primary amino group is, for example, a phthaloyl group which may be removed by treatment with an alkylamine, for example dimethylaminopropylamine, or with hydrazine.
A suitable protecting group for a hydroxy group is, for example, an acyl group, for example an alkanoyl group such as acetyl, an aroyl group, for example benzoyl, or an arylmethyl group, for example benzyl. The deprotection conditions for the above protecting groups will necessarily vary with the choice of protecting group. Thus, for example, an acyl group such as an alkanoyl or an aroyl group may be removed, for example, by hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide. Alternatively an arylmethyl group such as a benzyl group may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon.
A suitable protecting group for a carboxy group is, for example, an esterifying group, for example a methyl or an ethyl group which may be removed, for example, by hydrolysis with a base such as sodium hydroxide, or for example a t-butyl group which may be removed, for example, by treatment with an acid, for example an organic acid such as trifluoroacetic acid, or for example a benzyl group which may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon.
For examples of protecting groups see one of the many texts on the subject, for example, xe2x80x9cProtective Groups in Organic Synthesisxe2x80x9d by Theodora Green (John Wiley and Sons). The protecting groups may be removed at any convenient stage in the synthesis using conventional techniques well known in the chemical art, such methods being chosen so as to effect removal of the protecting group with minimum disturbance of groups elsewhere in the molecule.
When a pharmaceutically-acceptable salt of a compound of the formula (I) is required, it may be obtained, for example, by reaction of said compound with the appropriate acid (which affords a physiologically acceptable anion), or with the appropriate base (which affords a physiologically acceptable cation), or by any other conventional salt formation procedure.
When an optically active form of a compound of the formula (I) is required, it may be obtained, for example, by carrying out one of the aforesaid procedures using an optically active starting material or by resolution of a racemic form of said compound using a conventional procedure.
According to a further feature of the invention there is provided a compound of the formula (I), or a pharmaceutically acceptable salt or an in vivo hydrolysable ester thereof, for use in a method of treatment of the human or animal body by therapy.
According to a further feature of the present invention there is provided a method for producing an antibacterial effect in a warm blooded animal, such as man, in need of such treatment, which comprises administering to said animal an effective amount of a compound of the present invention, or a pharmaceutically acceptable salt, or an in vivo hydrolyzable ester thereof.
The invention also provides a compound of the formula (I), or a pharmaceutically acceptable salt, or an in vivo hydrolysable ester thereof for use as a medicament; and the use of a compound of the formula (I) of the present invention, or a pharmaceutically acceptable salt or an in vivo hydrolysable ester thereof, in the manufacture of a medicament for use in the production of an antibacterial effect in a warm blooded animal, such as man.
In order to use a compound of the formula (I) or a pharmaceutically acceptable salt or an in vivo hydrolysable ester thereof for the therapeutic treatment of mammals including humans, in particular in treating infection, it is normally formulated in accordance with standard pharmaceutical practice as a pharmaceutical composition.
Therefore in another aspect the present invention provides a pharmaceutical composition which comprises a compound of the formula (I) or a pharmaceutically acceptable salt or an in vivo hydrolysable ester thereof and a pharmaceutically acceptable diluent or carrier.
The pharmaceutical compositions of this invention may be administered in standard manner for the disease condition that it is desired to treat, for example by oral, rectal or parenteral administration. For these purposes the compounds of this invention may be formulated by means known in the art into the form of, for example, tablets, capsules, aqueous or oily solutions or suspensions, (lipid) emulsions, dispersible powders, suppositories, ointments, creams, drops and sterile injectable aqueous or oily solutions or suspensions.
In addition to the compounds of the present invention the pharmaceutical composition of this invention may also contain or be co-administered with one or more known drugs selected from other clinically useful antibacterial agents (for example xcex2-lactams or aminoglycosides). These may include penicillins, for example oxacillin or flucloxacillin and carbapenems, for example meropenem or imipenem, to broaden the therapeutic effectiveness. Compounds of this invention may also contain or be co-administered with bactericidal/permeability-increasing protein product (BPI) or efflux pump inhibitors to improve activity against gram negative bacteria and bacteria resistant to antimicrobial agents.
A suitable pharmaceutical composition of this invention is one suitable for oral administration in unit dosage form, for example a tablet or capsule which contains between 100 mg and 1 g of the compound of this invention.
In another aspect a pharmaceutical composition of the invention is one suitable for intravenous, subcutaneous or intramuscular injection.
Each patient may receive, for example, a daily intravenous, subcutaneous or intramuscular dose of 5 mgkgxe2x88x921 to 20 mgkgxe2x88x921 of the compound of this invention, the composition being administered 1 to 4 times per day. The intravenous, subcutaneous and intramuscular dose may be given by means of a bolus injection. Alternatively the intravenous dose may be given by continuous infusion over a period of time. Alternatively each patient will receive a daily oral dose which is approximately equivalent to the daily parenteral dose, the composition being administered 1 to 4 times per day.
The following illustrate representative pharmaceutical dosage forms containing the compound of formula (I) or a pharmaceutically-acceptable salt thereof (hereafter compound X), for therapeutic or prophylactic use in humans:
(b)
(c)
Buffers, pharmaceutically-acceptable cosolvents such as polyethylene glycol, polypropylene glycol, glycerol or EtOH or complexing agents such as hydroxy-propyl xcex2 cyclodextrin may be used to aid formulation.
Note
The above formulations may be obtained by conventional procedures well known in the pharmaceutical art. The tablets (a)-(c) may be enteric coated by conventional means, for example to provide a coating of cellulose acetate phthalate.
Antibacterial Activity
The pharmaceutically-acceptable compounds of the present invention are useful antibacterial agents having a good spectrum of activity in vitro against standard Gram-positive organisms, which are used to screen for activity against pathogenic bacteria. Notably, the pharmaceutically-acceptable compounds of the present invention show activity against enterococci, pneumococci and methicillin resistant strains of S. aureus and coagulase negative staphylococci. The antibacterial spectrum and potency of a particular compound may be determined in a standard test system.
The antibacterial properties of the compounds of the invention may also be demonstrated in-vivo in conventional tests.
The following results were obtained on a standard in-vitro test system. The activity is described in terms of the minimum inhibitory concentration (MIC) determined by the agar-dilution technique with an inoculum size of 104 CFU/spot.
Staphylococci were tested on agar, using an inoculum of 104 CFU/spot and an incubation temperature of 37xc2x0 C. for 24 hoursxe2x80x94standard test conditions for the expression of methicillin resistance.
Streptococci and enterococci were tested on agar supplemented with 5% defibrinated horse blood, an inoculum of 104 CFU/spot and an incubation temperature of 37xc2x0 C. in an atmosphere of 5% carbon dioxide for 48 hoursxe2x80x94blood is required for the growth of some of the test organisms.
When tested in the above in-vitro tests the compounds of this invention give MICs in the range 0.001-256 xcexcg/ml.
The following data was obtained for Example 10